WO2011110597A1 - Procédé de production de ranélate de strontium - Google Patents

Procédé de production de ranélate de strontium Download PDF

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Publication number
WO2011110597A1
WO2011110597A1 PCT/EP2011/053546 EP2011053546W WO2011110597A1 WO 2011110597 A1 WO2011110597 A1 WO 2011110597A1 EP 2011053546 W EP2011053546 W EP 2011053546W WO 2011110597 A1 WO2011110597 A1 WO 2011110597A1
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formula
compound
acid
vii
alkyl
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PCT/EP2011/053546
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German (de)
English (en)
Inventor
Stefanie Ackermann
Uwe Jens Albrecht
Vit Lellek
Krzysztof Hoffman
Marcin Sawicki
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Azad Pharmaceutical Ingredients Ag
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Publication of WO2011110597A1 publication Critical patent/WO2011110597A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a novel process for the preparation of strontium ranelate of the formula (I)
  • Strontium-5- [bis (carboxymethyl) amino] -2-carboxy-4-cyanothiophene-3-acetate and its hydrates, and novel intermediates for their preparation.
  • Strontium ranelate and its hydrates have valuable pharmacological and therapeutic properties and are useful for the treatment and prevention of bone diseases. They are used in particular for the treatment and prevention of osteoporosis and osteoarthritis.
  • Strontium ranelate, the preparation and the therapeutic use of strontium ranelate and its tetrahydrate, heptahydrate and octahydrate are known from EP 0 415 850 A1.
  • EP 0 813 869 A1 describes the use of strontium ranelate for the treatment of osteoarthritis.
  • the principle was first described by Gewald, Schinke and Böttcher in Chemische Berichte, volume 99, pages 94-100 (1966) and in Chemische Berichte, volume 99, pages 2712-2715 (1966) and later by M. Wierzbicki, D Cagniant, P. Cagniant in Bulletin de la Societe Chimique de France, Nos. 7-8 (1975) pages 1786-1792 applied to the derivatives described above.
  • this reaction is carried out by double alkylation of the amino group with a 2-haloalkyl ester, for example ethyl bromoacetate or bromoacetic acid, then saponified to the desired strontium ranelate using strontium hydroxide or sodium hydroxide followed by ion exchange using strontium chloride (Scheme 2).
  • a 2-haloalkyl ester for example ethyl bromoacetate or bromoacetic acid
  • the alkylation is 8 -C conducted 0 quaternary ammonium compound in the presence of a catalytic C to reduce the response time of the alkylation to a few hours while increasing the reaction yield.
  • yields of 85% are obtained with a purity of> 98% for the alkylation with methyl bromoacetate.
  • the disadvantage of the processes described above is the formation of undesirable side reactions that occur in the alkaline saponification of the esters in the last stage, and the unsatisfactory yields of strontium ranelate. Due to acidic hydrogen atoms in the 2-position of the esters, under basic conditions not only their saponification but simultaneously also intramolecular cyclization with the nitrile group occurs. This intramolecular cyclization product leads by decarboxylation to other undesirable by-products.
  • strontium ranelate is obtained by reacting the tetraester with strontium hydroxide in a yield of 96% and a purity of> 98%.
  • the saponification is described starting from the tetraester by reaction with lithium bases, such as lithium hydroxide and lithium carbonate and subsequent treatment with strontium chloride, wherein strontium ranelate in a yield of 84.6% with a purity of> 99.5 % is obtained.
  • lithium bases such as lithium hydroxide and lithium carbonate
  • strontium chloride wherein strontium ranelate in a yield of 84.6% with a purity of> 99.5 % is obtained.
  • the object of the present invention was therefore to provide an alternative process for the preparation of strontium ranelate and its hydrates, with which strontium ranelate and its hydrates are obtained in higher yields at high purities.
  • strontium ranelate of the formula (I) (Distrontium-5- [bis (carboxymethyl) amino] -2-carboxy-4-cyanthiophene-3-acetate) and its hydrates are obtained by a process (variant A), which comprises the following steps: a) reaction of a compound of the formula (II),
  • Ri is C 1 -C 4 -alkyl, with malononitrile of the formula (III)
  • R 2 is C 1 -C 4 -alkyl or benzyl, in the presence of a heterogeneous base, in the presence of an organic solvent and in the presence of catalytic amounts of water, to give a compound of the formula (VI)
  • the process step d) is independent of the overall process of variant A new, if Ri is ethyl and also the subject of the invention.
  • the saturated hydrocarbon chains of CC 4 alkyl are each straight-chain or branched.
  • C 1 -C 4 -alkyl is preferably methyl, ethyl, n- or i-propyl, n-, sec-, i- or tert-butyl, in particular methyl, ethyl or tert-butyl.
  • Benzyl stands for the phenylmethyl group -CH 2 -C 6 H 5 .
  • X is bromine or chlorine, in particular bromine.
  • Ri is particularly preferably ethyl.
  • R 2 particularly preferably represents tert-butyl or benzyl.
  • the temperature can vary over a wide range.
  • Process step a) is generally carried out at temperatures of 50 ° C to 90 ° C, preferably at temperatures of 75 ° C to 85 ° C.
  • Suitable diluents for carrying out process step a) according to the invention are, by way of example and by way of preference, alcohols, such as ethanol or butanol; Ethers such as tetrahydrofuran or methyltetrahydrofuran; Esters, such as ethyl acetate; aromatic hydrocarbons such as chlorobenzene; polar non-protic solvents such as dimethylformamide, N-methylpyrrolidone or dimethylacetamide into consideration.
  • the solvent dimethylacetamide (DMA) is preferably used in process step a).
  • Process step a) according to the invention is carried out in the presence of an organic base or a heterogeneous inorganic base.
  • Suitable organic bases are all customary organic bases. These include, by way of example and by way of preference, tertiary amines, such as, for example, trimethylamine, triethylamine, tributylamine, N, N-dimethylethylamine, N, N-diisopropylethylamine, ⁇ , ⁇ -dimethylbenzylamine, pyridine, piperidine, N-methylpiperidine, N- Methylmorpholine, N, N-dimethylaminopyridine, N-methylethanolamine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU).
  • DABCO diazabicyclooctane
  • DBN diazabicyclononene
  • DBU diaza
  • Heterogeneous inorganic bases are all heterogeneous inorganic bases. These include, by way of example and by way of preference, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; Alkali metal bicarbonates, such as sodium bicarbonate,
  • process step a) triethylamine is preferably used.
  • the process step a) according to the invention is carried out in particular as described below.
  • process step a) the compound of formula (II) is dissolved in dimethylacetamide and treated with malononitrile. Subsequently, triethylamine and sulfur are added.
  • Process step b) is generally carried out at temperatures of 40 ° C to 80 ° C, preferably at temperatures of 50 ° C to 70 ° C, more preferably at temperatures of 55 ° C to 65 ° C.
  • Process step b) is carried out in the presence of a heterogeneous base.
  • heterogeneous bases are suitable. These include, by way of example and by way of preference, alkali metal carbonates, such as, for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; Alkali metal bicarbonates, such as sodium bicarbonate, disodium bicarbonate; Alkali metal phosphates such as potassium phosphate.
  • alkali metal carbonates such as, for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate
  • Alkali metal bicarbonates such as sodium bicarbonate, disodium bicarbonate
  • Alkali metal phosphates such as potassium phosphate.
  • Suitable diluents for carrying out process step b) are all inert organic solvents.
  • aromatic hydrocarbons such as toluene
  • Ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole
  • Nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile
  • Amides such as ⁇ , ⁇ -dimethylformamide, N-methylformanilide
  • chlorinated hydrocarbons such as methylene chloride
  • Sulfoxides such as dimethylsulfoxide
  • Sulfones ketones such as acetone or methyl ethyl ketone.
  • acetone or methyl ethyl ketone is used.
  • step b) As catalytic amounts of water in step b) 0.1-5 eq. Water, preferably 0.2-2.5 eq. Water, more preferably 0.3-1 eq. Water used (1 eq means 1 equivalent).
  • the method step b) is carried out in particular as described below.
  • the compound of formula (V) is dissolved in an organic solvent and using a heterogeneous base, for example potassium carbonate, by means of 2-haloacetic acid-ieri-butyl ester, for example 2-bromoacetic acid-fe / t-butyl ester, in the Heat alkylated.
  • a heterogeneous base for example potassium carbonate
  • the heterogeneous base is filtered off and the desired product, the compound of the formula (VI), is crystallized by means of an antisolvent, for example water / ethanol.
  • an antisolvent for example water / ethanol.
  • process step c) the compound (VI) isolated according to process step b) is converted into the diacid by means of an acid in an organic solvent, i. a compound of formula (VII).
  • the diacid may be further purified by recrystallization to subsequently obtain high purity strontium ranelate.
  • the process step c) according to the invention is generally carried out at temperatures of 20 ° C to 100 ° C, preferably at temperatures of 70 ° C to 80 ° C.
  • the process step c) according to the invention is carried out in the presence of a strong organic acid.
  • a strong organic acid include, by way of example and by way of preference, arylsulfonic acids such as, for example, toluenesulfonic acid, alkylsulfonic acids such as methanesulfonic acid, haloalkylsulfonic acids such as trifluoromethanesulfonic acid, trichloroacetic acid or trifluoroacetic acid.
  • Methane sulfonic acid or toluenesulfonic acid is preferably used in process step c).
  • Suitable diluents for carrying out process step c) are the organic solvents mentioned for process step b).
  • Process step c) is preferably carried out in toluene.
  • the method step c) is described in particular as follows carried out.
  • the compound of the formula (VI) is reacted in an organic solvent, for example toluene, by means of a strong organic acid, for example methanesulfonic acid, to give the corresponding diacid of the formula (VII) (eg compound 3) and after the end the reaction directly isolated.
  • an organic solvent for example toluene
  • a strong organic acid for example methanesulfonic acid
  • the process step d) according to the invention is generally carried out at temperatures of 10 ° C to 100 ° C, preferably at temperatures of 15 ° C to 25 ° C or at 70 to 90 ° C.
  • suitable strontium salts are strontium chloride, strontium bromide or strontium hydroxide.
  • Strontium chloride is preferably used.
  • the compound of the formula (VII) is reacted with an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; or sodium bicarbonate, preferably with dilute sodium hydroxide saponified to the tetrasodium salt and transferred by ion exchange with strontium salts directly into the desired strontium ranelate and crystallized.
  • an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide; or sodium bicarbonate, preferably with dilute sodium hydroxide saponified to the tetrasodium salt and transferred by ion exchange with strontium salts directly into the desired strontium ranelate and crystallized.
  • strontium ranelate of the formula (I) and its hydrates can be obtained by a process (variant B) comprising the process steps a), b) and c) described above, and after process step c)
  • Process steps e) and f) comprises: e) reacting a compound of the formula (VII), in which Ri has the abovementioned meaning, with a base in an amount corresponding to 2 moles per mole of the compound of the formula (VII) a dialkali metal salt of the formula (VIII),
  • A is preferably Na.
  • the compounds of formula (VIII) are new and also the subject of Invention. Preference is given to compounds of the formula (VIII) in which R 1 is ethyl and A is Na.
  • strontium ranelate of the formula (I) is obtained in an overall yield of about 64%. receive. Consequently, surprisingly, a significantly higher total yield is obtained by the process of variant B according to the invention.
  • step e the diacid (compound of formula (VII)) is treated under mild reaction conditions by reaction with 2 eq.
  • Base e.g. Sodium hydroxide, sodium bicarbonate, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide, converted into the corresponding disodium salt of the formula (VIII).
  • Base e.g. Sodium hydroxide, sodium bicarbonate, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide
  • the process step e) according to the invention is carried out in the presence of a suitable base.
  • a suitable base As such, all customary inorganic bases are suitable.
  • Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal bicarbonates such as sodium bicarbonate used.
  • Sodium hydroxide is preferably used in process step e).
  • Process step e) is carried out under very mild conditions, e.g. with sodium hydroxide, carried out at room temperature.
  • step f) the reaction of the dialkali metal salt of the formula (VIII) with a further 2.1 eq.
  • Base eg NaOH
  • strontium for example strontium hydroxide or strontium chloride
  • strontium ranelate of the formula (I) and its hydrates can be obtained by a process (variant C) comprising the process steps a) and b) described above, the process step g) described below and the process step d described above g) reacting a compound of the formula (VI) in which R 1 has the abovementioned meaning and R 2 is benzyl, with hydrogen in the presence of a heterogeneous catalyst and in the presence of a diluent to give a compound of the formula (VII), in which Ri and R 2 have the meanings given above.
  • process step g starting from the dibenzyl ester of the formula (VI) in which R 2 is benzyl, by hydrogenolysis with a catalyst, in particular with Pd / C and hydrogen selectively to arrive at the compound of formula (VII) and thereby to avoid the side reaction of the cyclization and decarboxylation, so that high yields are obtained.
  • the process step g) is new and also the subject of the invention.
  • Suitable diluents in process step g) are alcohols such as methanol and ethanol or ethers such as tetrahydrofuran (with or without combination with water). Ethanol is particularly preferably used.
  • the process step g) is carried out in the presence of a heterogeneous catalyst.
  • Suitable heterogeneous catalysts are, for example, palladium / C, palladium / aluminum oxide, palladium / barium carbonate, palladium / barium sulfate, palladium / strontium carbonate, platinum / C or platinum / aluminum oxide.
  • palladium on carbon is preferably used.
  • the process step g) according to the invention is carried out in particular as described below.
  • the compound of the formula (VI) in which R 2 is benzyl is dissolved in an organic solvent and hydrogenated by means of a catalyst under hydrogen pressure to give the compound of the formula (VII).
  • the process of variants A, B and C according to the invention makes it possible to produce high-purity strontium ranelate and its hydrates in high yields, with optional purification possibilities being available over various stages. Based on the Impurity profile of the intermediates, various combinations of intermediate isolations and purification steps can be applied to obtain optimum yield and purity. Examples

Abstract

L'invention concerne un nouveau procédé de production de ranélate de strontium de formule (I) (distrontium-5-[bis(carboxyméthyl)amino]-2-carboxy-4-cyanthiophén-3-acétate) et de ses hydrates ainsi que de nouveaux produits intermédiaires pour leur production.
PCT/EP2011/053546 2010-03-11 2011-03-09 Procédé de production de ranélate de strontium WO2011110597A1 (fr)

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EP10156264 2010-03-11
EP10156264.3 2010-03-11

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WO2011110597A1 true WO2011110597A1 (fr) 2011-09-15

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415850A1 (fr) 1989-09-01 1991-03-06 Adir Et Compagnie Sels de métaux bivalents de l'acide N, N-di(carboxyméthyl)amino-2 cyano-3 carboxyméthyl-4 carboxy-5 thiophène,leur procédé de préparation et les compositions pharmaceutiques les renfermant
EP0813869A1 (fr) 1996-06-17 1997-12-29 Adir Et Compagnie Utilisation de sels de strontium pour le traitement de l'arthrose
US20040063972A1 (en) 2002-09-24 2004-04-01 Lucile Vaysse-Ludot Process for the industrial synthesis of strontium ranelate and its hydrates
US20060142596A1 (en) 2002-09-24 2006-06-29 Les Laboratoires Servier Process for the industrial synthesis of the methyl diester of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and application to the synthesis of bivalent salts of ranelic acid and their hydrates
WO2007020527A2 (fr) 2005-08-19 2007-02-22 Glenmark Pharmaceuticals Limited Procede de preparation de ranelate de strontium
US20090082578A1 (en) 2007-09-26 2009-03-26 Les Laboratoires Servier Process for the synthesis of strontium ranelate and its hydrates

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0415850A1 (fr) 1989-09-01 1991-03-06 Adir Et Compagnie Sels de métaux bivalents de l'acide N, N-di(carboxyméthyl)amino-2 cyano-3 carboxyméthyl-4 carboxy-5 thiophène,leur procédé de préparation et les compositions pharmaceutiques les renfermant
EP0813869A1 (fr) 1996-06-17 1997-12-29 Adir Et Compagnie Utilisation de sels de strontium pour le traitement de l'arthrose
US20040063972A1 (en) 2002-09-24 2004-04-01 Lucile Vaysse-Ludot Process for the industrial synthesis of strontium ranelate and its hydrates
US20060142596A1 (en) 2002-09-24 2006-06-29 Les Laboratoires Servier Process for the industrial synthesis of the methyl diester of 5-amino-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid, and application to the synthesis of bivalent salts of ranelic acid and their hydrates
WO2007020527A2 (fr) 2005-08-19 2007-02-22 Glenmark Pharmaceuticals Limited Procede de preparation de ranelate de strontium
US20090082578A1 (en) 2007-09-26 2009-03-26 Les Laboratoires Servier Process for the synthesis of strontium ranelate and its hydrates

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMISCHE BERICHTE, 1966, pages 2712 - 2715
GEWALD; SCHINKE; BÖTTCHER, CHEMISCHE BERICHTE, 1966, pages 94 - 100
M. WIERZBICKI; D. CAGNIANT; P. CAGNIANT, BULLETIN DE LA SOCIETE CHIMIQUE DE FRANCE, 1975, pages 1786 - 1792

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